title: The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to severe, nonalcoholic steatohepatitis (NASH) in 7%-14% of the U.S. population through a second "hit" in the form of increased oxidative stress and inflammation. Endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR) are triggered when high levels of lipids and misfolded proteins alter ER homeostasis creating a lipotoxic environment within NAFLD livers. The objective of this study was to determine the coordinate regulation of ER stress-associated genes in the progressive stages of human NAFLD. Human liver samples categorized as normal, steatosis, NASH (Fatty), and NASH (Not Fatty) were analyzed by individual Affymetrix GeneChip Human 1.0 ST microarrays, immunoblots, and immunohistochemistry. A gene set enrichment analysis was performed on autophagy, apoptosis, lipogenesis, and ER stress/UPR gene categories. An enrichment of downregulated genes in the ER stress-associated lipogenesis and ER stress/UPR gene categories was observed in NASH. Conversely, an enrichment of upregulated ER stress-associated genes for autophagy and apoptosis gene categories was observed in NASH. Protein expression of the adaptive liver response protein STC2 and the transcription factor X-box binding protein 1 spliced (XBP-1s) were significantly elevated among NASH samples, whereas other downstream ER stress proteins including CHOP, ATF4, and phosphorylated JNK and eIF2α were not significantly changed in disease progression. Increased nuclear accumulation of total XBP-1 protein was observed in steatosis and NASH livers. The findings reveal the presence of a coordinated, adaptive transcriptional response to hepatic ER stress in human NAFLD.
authors.affiliation: * Department of Pharmacology and Toxicology and.
authors.forename: April D
authors.initials: AD
authors.lastname: Lake
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.forename: Brieanna
authors.initials: B
authors.lastname: Flores-Keown
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D015153:Blotting, Western; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000737:chemistry* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D020411:Oligonucleotide Array Sequence Analysis; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human
keywords: endoplasmic reticulum stress response mechanisms.; lipotoxicity; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis